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Updated: Jul 6, 2026

Curation of Computational Chemical Libraries Demonstrated with Alpha-Amino Acids
Published on: April 13, 2022
Amino acid alphabet size in protein evolution experiments: better to search a small library thoroughly or a large
Enrique Muñoz1, Michael W Deem
1Department of Bioengineering, Rice University, Houston, TX 77005-1892, USA.
Abstract:
We compare the results obtained from searching a smaller library thoroughly versus searching a more diverse, larger library sparsely. We study protein evolution with reduced amino acid alphabets, by simulating directed evolution experiments at three different alphabet sizes: 20, 5 and 2. We employ a physical model for evolution, the generalized NK model, that has proved successful in modeling protein evolution, antibody evolution and T-cell selection. We find that antibodies with higher affinity are found by searching a library with a larger alphabet sparsely than by searching a smaller library thoroughly, even with well-designed reduced libraries. We also find ranked amino acid usage frequencies in agreement with observations of the CDR-H3 variable region of human antibodies.
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